Homocystinuria due to cystathionine beta-synthase (CBS) deficiency causes ectopia lentis, Marfanoid habitus, thromboembolism, and intellectual disability. In CBS deficiency, plasma homocysteine and methionine are elevated. High-dose pyridoxine treatment is effective in approximately 50% of patients because:
- A Pyridoxine increases methionine synthase activity bypassing CBS
- B Pyridoxine inhibits the transsulfuration pathway reducing homocysteine
- C Pyridoxal phosphate is a cofactor for CBS; mutations with residual activity respond to cofactor saturation ✓
- D Pyridoxine stimulates betaine-homocysteine methyltransferase to clear homocysteine
Explanation
Cystathionine beta-synthase catalyses condensation of homocysteine + serine → cystathionine, using pyridoxal phosphate (PLP, the active form of vitamin B6) as a covalently-bound cofactor. In pyridoxine-responsive CBS deficiency, the mutant enzyme has reduced affinity for PLP; pharmacological doses of pyridoxine saturate the cofactor binding site, stabilising enzyme conformation and partially restoring catalytic activity. Pyridoxine-non-responsive patients require betaine (alternative remethylation) and methionine restriction. Measuring homocysteine after pyridoxine loading differentiates the two groups.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.